Potassium Phosphate, Tribasic → [3-(3,5-Difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amine

HRID 1890753

Reaktionsgleichung

Reaktionsgleichung von HRID 1890753
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:12]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]1)[CH2:7]2.[F:19][C:20]1[C:21]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=2[CH3:34])[NH2:30])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:19][C:20]1[C:21]([C:27]2[CH:28]=[C:29]([NH:30][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][N:6]([CH:12]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]3)[CH2:7]4)[CH:31]=[CH:32][C:33]=2[CH3:34])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1

Komponenten

7

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 583178905-Bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolineHCID 583179983-(3,5-Difluoropyridin-2-yl)-4-methylaniline

Produkt 1

HCID 57493333[3-(3,5-Difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amineAusbeute 65 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To the reaction vessel containing 5-bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinoline (50 mg, 0.15 mmol), 3-(3,5-difluoropyridin-2-yl)-4-methylaniline (33 mg, 0.15 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), Xantphos (16 mg, 0.028 mmol) and K3PO4 (74 mg, 0.35 mmol) is added anhydrous dioxane (1 mL). The vessel is flushed with nitrogen, sealed and heated to 100° C. for 15 hours. The reaction is then cooled to ambient temperature, filtered through a celite pad to remove salt. The filtrate is concentrated and purified by silica gel flash chromatography to afford [3-(3,5-difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amine as an off-white solid (45 mg, 65%). MS m/z 470.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ8.67 (d, 1H, J=2.4 Hz), 7.39 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.12 (m, 2H), 7.00 (dd, 1H, J1=8.0 Hz, J2=2.4 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.75 (d, 1H, J=7.2 Hz), 3.79 (d, 1H, J=19.2 Hz), 3.71 (d, 1H, J=19.2 Hz), 3.47 (m, 2H), 3.34 (m, 1H), 3.18 (m, 2H), 2.82 (m, 2H), 2.72 (m, 2H), 2.47 (m, 1H), 2.17 (m, 1H), 2.11 (s, 3H).

Aufarbeitung

  1. customThe vessel is flushed with nitrogen
  2. customsealed
  3. temperatureThe reaction is then cooled to ambient temperature
  4. filtrationfiltered through a celite pad
  5. customto remove salt
  6. concentrationThe filtrate is concentrated
  7. custompurified by silica gel flash chromatography

Quellen und Nachweise

ORD-Eintrag
ord-9981a6cc80d0421fbd5260c88e7097a6
Quelldatensatz
uspto-grants-2013_08
Patentnummer
US08507491B2

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